Asthma is a chronic inflammatory disease of the respiratory airways and is becoming epidemic in the United States. Oxidative stress plays an important role in exacerbation of airway inflammation and overall disease symptom. Although it has been shown that the levels of vitamin E and ascorbate were decreased in asthmatics, the potential to use antioxidants in the therapy of asthma has not been well explored. The proposed studies in project 3 is part of the synergistic effort for investigating the utility of natural antioxidants as complementary and alternative medicines (CAMs) in the treatment of asthma. During inflammation, several pro-inflammatory mediators including prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), cytokines and chmokines, play central roles in regulating inflammatory response and asthma. We propose to use various forms of vitamin E and polyphenols as the starting candidates based on the recent studies by us and the others. We have discovered that gamma-tocopherol, the major form of vitamin E in diets, has anti-inflammatory activity by inhibiting PGE2 and LTB4 as well as TNF-a. It has been shown that polyphenols like genistein and resveratrol potentiate the cytokine expression in certain cellular system through NF-kappaB regulated gene expression. In addition, ascorbate, genistein and reseveratrol exhibit beneficial effects on regulating airway epithelial fluid secretion. These observations lead to the current hypothesis that these natural antioxidants, and their combinations may be useful as CAMs in the treatment of asthma. Project 3 aims to discover candidate CAM therapies on a molecular, cellular and mechanistic basis to assess the ability of potential CAMs to inhibit oxidative damage from myeloperoxidase and eosinophil peroxidase, generation of eicosanoids by cyclooxygenase and lipoxygenase, NF-kappaB and MAP kinase mediated gene regulation and cytokine formation, and to modulate Na+ and CI- ion channels, transepithelial barrier function and H+ conductive pathways of the airway epithelium. Our studies will provide the scientific basis for our collaborators, Drs Wagner & Harkema at MSU to test CAMs in rodent models and Drs Peden, Alexis, Bromberg & Patel at UNC in Phase I Clinical Screening of CAMs therapy.